LEVODOPA PHARMACOKINETICS AND PHARMACODYNAMICS

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The initial response to levodopa in Parkinson's disease (PD) is generally one of marked, sustained improvement in motor function. With long-term levodopa treatment, this response is replaced by fluctuating response which may be very disabling and is resistant to therapeutic manipulations. We hypothesize that the motor function in levodopa-treated PD is a product of the short-duration response (SDR) to levodopa, with a half-life of hours; the long-duration response (LDR) to levodopa, with a half-life of days; and endogenous dopamine production. The initial, good response to levodopa is dominated by the LDR. The development of fluctuations reflects reduction of the LDR and endogenous dopamine synthesis caused by disease progression and, possible, levodopa treatment. Further, we hypothesize that the diurnal motor variation noted as morning improvement and evening deterioration in motor function in PD may be a marker of impaired endogenous dopamine synthesis. This proposal switches the emphasis from the SDR which has dominated the thinking about the motor response to levodopa to the LDR which has been largely ignored. The aims of this clinical study are: 1.) Examine the changes in the SDR and LDR during the first 4 years of levodopa treatment and correlate them with the emergence of clinically apparent motor fluctuations to determine the relative contribution of the SDR and LDR to fluctuations. 2.) Examine the SDR and LDR in dopa-responsive dystonia (DRD), a form of parkinsonism in which dopamine synthesis is impaired but dopamine storage is intact, to determine the importance of dopamine storage to the SDR and LDR. 3.) Determine if apomorphine, a dopamine agonist, will sustain the LDR to establish if the LDR is a pre- or a postsynaptic action. 4.) Examine the diurnal motor variation in PD, DRD and normal controls to determine if diurnal motor variation is a marker for impaired dopamine neurotransmission. Also determine is motor activity influences the diurnal pattern in PD to suggest that depletion of dopamine could underlie the phenomenon. Our overall goal is to understand the fluctuating response to levodopa. The major thrust for this grant period is to determine the contribution of the LDR to the benefits of levodopa treatment and to suggest methods to selectively induce or augment the LDR.